Process for the preparation of 5-substituted-1-(4-fluorophenyl)-1,3-dihydroisobenzofurans

ABSTRACT

The present invention provides a process for the preparation of a 5-substituted-1-(4-fluorophenyl)-1,3-dihydro-isoben-zofuran of Formula (2), an intermediate for the manufacture of citalopram, which process comprises: (a) carrying out a Grignard reaction on a corresponding 5-substituted phthalide of Formula (3) in a co-solvent system, comprising adding (i) prepared 4-fluorophenyl magnesium halide in an ether solvent to (ii) the 5-substituted phthalide in a suitable organic co-solvent to the ether solvent, to form a corresponding 4-substituted-2-hydroxymethyl-4′-fluorobenzophenone of Formula (4); (b) carrying out a ketone reduction of the 4-substituted-2-hydroxymethyl-4′-fluorobenzophenone of Formula (4) following the Grignard reaction, to form a corresponding 4-substituted-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanol of Formula (5); and (c) carrying out a cyclisation reaction on the 4-substituted-2 hydroxymethylphenyl-1-(4-fluorophenyl) methanol of Formula (5) following the reduction reaction, to form said intermediate of Formula (2); wherein R represents Br or CN.

FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of5-substituted-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran (2a, 2b), animportant intermediate in the preparation of citalopram, from5-substituted phthalides.

BACKGROUND TO THE INVENTION

Citalopram and its pharmaceutically acceptable acid addition salts, suchas the hydrogen bromide salt shown in Formula 1 below, described in U.S.Pat. No. 4,650,884, are valuable anti-depressant drugs with few sideeffects and have been commercially available for a number of years.

Many processes for the manufacture of citalopram and its acid additionsalts are disclosed in the literature, from which it is apparent that5-substituted phthalanes(5-substituted-1-(4-fluorophenyl)-1,3-dihydroisobenzofurans of Formulae2a and 2b) are very important key intermediates in the manufacture ofcitalopram.

Various processes for the preparation of5-substituted-1-(4-fluorophenyl)-1,3-dihydroisobenzofurans have beendescribed in the prior art, according to Scheme 1 shown below:

For example, the process described in U.S. Pat. No. 4,136,193 involvesthe reaction of 4-fluorophenyl magnesium bromide, generated in situ bythe reaction of 4-fluorobromobenzene with magnesium in anhydrous diethylether solvent medium, with 5-bromophthalide (Formula 3a) intetrahydrofuran medium. After completion of the reaction, the reactionmass is quenched with aqueous ammonium chloride solution, followed bywork-up to provide the intermediate2-hydroxymethyl-4-bromo-4-fluorobenzophenone (hydroxymethyl-ketone ofFormula 4a). The hydroxymethylketone (4a) is then reduced with lithiumaluminium hydride in ether medium to provide4-bromo-2-hydroxymethylphenyl-(4-fluorophenyl)methanol (diol of Formula5a). The diol (5a) is then cyclised with aqueous phosphoric acid toproduce 5-bromophthalane(5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran, 2a) which is thenconverted to 5-cyanophthalane(5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran, 2b) by reactionwith cuprous cyanide.

The main drawback of this process is in the handling of diethyl ether atplant level. Diethyl ether is a highly volatile, inflammable solventhaving a very low flash point. Hence, efficient recovery and recyclingof the solvent at the commercial level is not possible. Furthermore, thehandling of lithium aluminium hydride, a highly pyrophoric,moisture-sensitive material, is also very difficult at plant level.Therefore, the process is not commercially attractive.

U.S. Pat. No. 6,291,689 discloses a process for preparing5-cyanophthalane (5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran,2b) in which a solution of 4-fluorophenyl magnesium bromide, preparedfrom 4-bromofluorobenzene and magnesium turnings in dry tetrahydrofuran,is added drop-wise to a suspension of 5-cyanophthalide (3b) in drytetrahydrofuran below 5° C. After the addition is completed, ethanol isadded to the reaction mixture and a large excess of sodium borohydride(2.0 molar equivalents) is added lot-wise to the reaction mixture. Thereaction mixture is stirred overnight at room temperature and then about⅔ of the solvent is removed under vacuum. Water is added to the reactionmixture and the resulting solution is extracted with ethyl acetate. Theethyl acetate is then distilled off under vacuum to provide the crudediol 4-cyano-2-hydroxymethylphenyl-(4-fluorophenyl)methanol (5b) as anoil. The oil is purified by column chromatography to produce the purediol (5b) as a solid. However, the oil as such is cyclised in thepresence of 60% phosphoric acid solution at 80° C. for 3 hours. The acidsolution is then extracted twice with toluene and the organic layer isseparated. The combined toluene layer is distilled under vacuum to getthe oily residue. The oily residue is then crystallized in ethanol toproduce the pure 5-cyanophthalane (2b). The overall yield is 29% from5-cyanophthalide.

The major drawbacks of this process are that:

-   -   i) an expensive solvent, anhydrous tetrahydrofuran, is used        which, under the reaction work-up conditions, is difficult to        recover and recycle, and thus makes the process uneconomical;    -   ii) different solvents (e.g. ethyl acetate and toluene) are used        at different stages and hence the process becomes commercially        unattractive; and    -   iii) a large excess of sodium borohydride is used during the        reduction stage, making the process potentially dangerous.

The present invention seeks to address these problems and provides avery simple method according to Scheme 1 for the preparation of pure5-substituted phthalanes (2a,b) from 5-substituted phthalides (3a,b),without the isolation of any intermediate and with improved yield andquality of the product.

The present invention also provides a simple procedure for thepreparation of the diol (5b) of high purity, for example, greater than97% purity, which, on further cyclisation with a catalytic amount ofp-toluenesulfonic acid in an organic solvent, results in5-cyanophthalane (2b) of similar high purity.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, there is provideda process for the preparation of a5-substituted-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran of Formula 2,an intermediate for the manufacture of citalopram, which processcomprises:

-   -   (a) carrying out a Grignard reaction on a corresponding        5-substituted phthalide of Formula 3 in a co-solvent system,        comprising adding (i) prepared 4-fluorophenyl magnesium halide        in an ether solvent to (ii) the 5-substituted phthalide in a        suitable organic co-solvent to the ether solvent, to form a        corresponding        4-substituted-2-hydroxymethyl-4′-fluorobenzophenone of Formula        4,    -   (b) carrying out a ketone reduction of the        4-substituted-2-hydroxymethyl-4′-fluorobenzophenone of Formula 4        following the Grignard reaction, to form a corresponding        4-substituted-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanol        of Formula 5, and    -   (c) carrying out a cyclisation reaction on the        4-substituted-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanol        of Formula 5 following the reduction reaction, to form said        intermediate of Formula 2:        wherein R represents Br or CN.

Where the 5-substituted-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran is5-bromophthalane, the corresponding 5-substituted phthalide is5-bromophthalide. Where the5-substituted-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran is5-cyanophthalane, the corresponding 5-substituted phthalide is5-cyanophthalide.

According to a second aspect of the present invention, there is provideda process for preparation of4-bromo-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanol or4-cyano-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanol of Formula 5,which process comprises:

-   -   (a) carrying out a Grignard reaction on a corresponding        5-substituted phthalide of Formula 3 in a co-solvent system,        comprising adding (i) prepared 4-fluorophenyl magnesium halide        in an ether solvent to (ii) the 5-substituted phthalide in a        suitable organic co-solvent to the ether solvent, to form a        corresponding        4-substituted-2-hydroxymethyl-4′-fluorobenzophenone of Formula        4, and    -   (b) carrying out a ketone reduction of the        4-substituted-2-hydroxymethyl-4′-fluorobenzophenone of Formula 4        with sodium borohydride, to form        4-bromo-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanol or        4-cyano-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanol of        Formula 5:        wherein R represents Br or CN.

If desired, 4-cyano-2-hydroxymethylphenyl-(4-fluorophenyl)methanol maybe isolated as a solid directly from the reaction mixture with an HPLCpurity of 99%.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The process comprises a Grignard reaction, in which the molar ratio of4-fluorophenyl magnesium halide to the 5-substituted phthalidepreferably is 1:1 to 1.4:1.

Although tetrahydrofuran (THF) is the preferred ether solvent, othersthat may be used include 1,4-dioxane, diethylether or dimethoxyethane.

Preferably, the co-solvent is an aliphatic or aromatic chlorinatedsolvent or an aromatic hydrocarbon. Where the co-solvent is an aliphaticor aromatic chlorinated solvent, it is suitably selected from methylenedichloride, ethylene dichloride, trichloroethane, carbon tetrachloride,chloroform, chlorobenzene, dichlorobenzene, and mixtures thereof.Methylene dichloride and especially chloroform are particularlypreferred. As aromatic hydrocarbon co-solvents, toluene, benzene orxylene, or mixtures thereof, are preferred. Toluene is particularlypreferred.

Particularly preferably, the ether solvent and co-solvent are both dryand suitably the volumetric ratio of ether solvent to co-solvent isbetween 3:10 and 6:7. The lowest proportion of the ether solvent to theco-solvent is restricted by the tendency of the Grignard reagent toprecipitate out of solution.

The Grignard reaction is suitably carried out at a temperature of below10° C., preferably at a temperature from −6° C. to +6° C., and mostpreferably at a temperature from −6° C. to −2° C.

The process comprises a ketone reduction step following the Grignardreaction. The reducing agent for the reduction step is sodiumborohydride. Preferably about 0.25 to about 1.0 molar equivalents ofsodium borohydride are used. Particularly preferably only about 0.5molar equivalents of sodium borohydride are used. This starkly contraststo the prior art where an excess of sodium borohydride is required.

The process according to the first aspect further comprises carrying outa cyclisation reaction following the reduction reaction. The cyclisationreaction is carried out in presence of an inorganic acid or organicacid. Inorganic acids that may be used include aqueous phosphoric acidand aqueous sulfuric acid, but preferably aqueous hydrochloric acid,more preferably concentrated hydrochloric acid, is used. Organic acidsthat may be used include methanesulfonic acid, benzenesulfonic acid andpara-toluene sulfonic acid (PTSA). A particularly preferred organic acidis PTSA.

The amount of acid used is suitably a limited amount and preferably is acatalytic amount, i.e. not substantially more than the minimum amountrequired for catalysis of the cyclisation reaction. Where PTSA is used,it is suitably present in a catalytic amount of 5 to 10% w/w withrespect to the 5-substituted phthalide.

Advantageously, the entire process according to the first aspect of thepresent invention, comprising the Grignard reaction, reduction reactionand cyclisation reaction, may be carried out in a reaction vessel, evenjust one common vessel, without isolation of intermediates fromsolution.

In a preferred embodiment of the invention, starting from5-bromophthalide (3a), a solution of 4-fluorophenyl magnesium bromide isprepared from 4-bromofluorobenzene, magnesium turnings and catalyticamount of iodine in dry tetrahydrofuran (THF), and is added drop-wise toa suspension of 5-bromophthalide (3a, 1 molar equivalent) in a dryorganic co-solvent under nitrogen atmosphere at a temperature below 10°C., preferably −6° C. to +6° C., and most preferably −6° C. to −2° C.,over a period of 4-6 hours.

After the addition is completed, the reaction mixture is quenched with20% aqueous ammonium chloride solution, and the organic layer isseparated and diluted with methanol.

Then, sodium borohydride (0.5-1.0 molar equivalents, preferably 0.5molar equivalents) is added lot-wise to the reaction mixture at atemperature of below 25° C. and the reaction mixture is further stirredfor an additional 2 hours at the same temperature. After the completionof the reaction, water is added and the organic layer is separated. Theorganic layer is washed with 10% hydrochloric acid solution, water andthen concentrated under reduced pressure to obtain an oily residue.

The oily residue is then subjected to a cyclisation reaction in presenceof an inorganic acid or organic acid. A particularly preferred organicacid is para-toluene sulfonic acid (PTSA), and this is suitably used incatalytic amounts.

For example, to the oily residue, aqueous hydrochloric acid is added andthe mixture is heated to 60-70° C. for 2-3 hours. After the completionof the reaction, the reaction mixture is cooled to room temperature andextracted with an aliphatic or aromatic hydrocarbon, such as n-hexane,cyclohexane, benzene and toluene. The organic layer is washed withdilute sodium hydroxide solution and water. The organic layer is treatedwith activated charcoal, and concentrated under reduced pressure toprovide 5-bromophthalane (2a) having a purity of greater than 85%.

Alternatively and preferably, the oily residue is dissolved in anorganic solvent, for example in toluene, and a catalytic amount ofp-toluene sulfonic acid (5-10% w/w) is added. The resulting mixture isheated to 85-90° C. and water formed during the reaction is removedcontinuously by azeotropic distillation. After the completion of thereaction, the reaction mixture is washed with dilute sodium hydroxidesolution, water and finally the solvent is removed under reducedpressure to produce 5-bromophthalane (2a).

5-Bromophthalane (2a) can then be converted to 5-cyanophthalane (2b)using known procedures, without any further purification.

In a second embodiment, starting from 5-cyanophthalide (3b), a solutionof 4-fluorophenyl magnesium bromide in tetrahydrofuran is addeddrop-wise over a period of 4-6 hours to a suspension of 5-cyanophthalide(3b, 1 molar equivalent) in a dry organic solvent under nitrogenatmosphere below 10° C. (preferably −6° C. to +6° C., and mostpreferably −6° C. to −2° C.).

As in the first embodiment above, the dry organic co-solvent maysuitably be an aliphatic or aromatic chlorinated solvent such asmethylene dichloride, ethylene dichloride, chloroform or chlorobenzene,or may be an aromatic hydrocarbon such as benzene, toluene or xylene.

After the addition is completed, the reaction mixture is quenched with20% aqueous ammonium chloride solution the organic layer is separatedand diluted with methanol. Then sodium borohydride (0.5 molarequivalents) is added lot-wise to the reaction mixture below 25° C.(suitably 15° C. to 20° C.) and the reaction mixture is stirred foradditional 4-6 hours. Then the reaction mixture is quenched over waterand the organic layer is separated out. The organic layer is thenconcentrated completely under vacuum to provide a residue, which is usedwithout any further work up for the next stage. Alternatively, thereaction mixture is cooled to below 10° C. and the precipitated solid isfiltered to produce pure crystalline4-cyano-2-hydroxymethylphenyl-(4-fluorophenyl)methanol (5b) with morethan 98% purity by HPLC.

The residue/crystalline solid (5b) is taken in an organic solvent suchas toluene or methanol, preferably toluene, followed by cyclisation in30% aqueous hydrochloric acid. After the completion of the reaction, thereaction mass is cooled to 25-30° C. and extracted with toluene. Theorganic layer is treated with activated carbon and concentrated underreduced pressure. Isopropanol is added to the residue to provide whitecrystalline 5-cyanophthalane (2b) having a purity of more than 99% byHPLC. The cyclisation may also be carried out in toluene using acatalytic amount of p-toluenesulfonic acid (5-10% w/w with respect to5-cyanophthalide) to produce 5-cyanophthalane (2b). The overall yieldfrom 5-cyanophthalide to 5-cyanophthalane is 80%.

As indicated in Table 1 and Table 2 below, the present inventionestablishes that the presence of a co-solvent such as toluene orethylene dichloride (and also other co-solvents) with the main ethersolvent such as tetrahydrofuran yields a better quality of the5-substituted phthalanes (2a,b).

By the present invention, a single pot procedure has been developed forpreparing 5-substituted phthalanes (2a,b) from 5-substituted phthalides(3a,b) without the isolation of any intermediates, suitably usingp-toluenesulfonic acid as a catalyst for the cyclisation of the diol(5a,b).

In summary, there are several major advantages of the present inventionover the prior art procedures. First, dry tetrahydrofuran is anexpensive solvent and is used in large excess in the Grignard reactionin the prior art process. Under the reaction work-up conditions, therecovery and re-use of dry tetrahydrofuran is difficult. In the presentinvention, the use of tetrahydrofuran can be minimised by employing oneor more co-solvents, which are cheap and readily recoverable. Hence theprocess is made far more commercially attractive. Secondly, with the useof a co-solvent, the intermediates at each stage are easily takenfurther by simple work-up procedures without the need for isolation orpurification of any intermediates.

Furthermore, using the method of the present invention, 0.50 molarequivalents of sodium borohydride is sufficient to reduce thehydroxyketone (4a,b), as opposed to the excess (2.0 molar equivalents)of sodium borohydride used in the prior art processes.

In the final stage of the process, cyclisation with a catalytic amountof acid avoids any large excess of aqueous acidic effluent which isgenerated by the use of excess acid as described in the prior art.

The following examples serve to further illustrate the presentinvention:

EXAMPLE 1 Preparation of pure5-Bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (2a) UsingHalogenated Solvents

A solution of 4-fluorophenyl magnesium bromide prepared from 116 g4-fluoro bromobenzene (0.662 moles), 18.81 g, magnesium turnings (0.78moles) and 0.05 g Iodine in dry 300 ml tetrahydrofuran, is added to asuspension of 10 g 5-bromophthalide (0.469 moles) in 1000 ml methylenedichloride at −6 to −2° C. After the reaction is completed, the reactionmass is quenched with 100 ml 20% aqueous ammonium chloride solution. Theorganic layer is separated and diluted with 100 ml of methanol. Slowly,12 g of sodium borohydride (0.324 moles) is added in lots over a periodof one hour at below 25° C., and the temperature is maintained for anadditional hour.

The reaction mass is quenched with 200 ml ice water. The organic layeris separated washed with dilute hydrochloric acid (10%, 100 ml) and thenwith 100 ml water. The organic layer is dried over anhydrous sodiumsulfate and concentrated under reduced pressure to produce4-bromo-2-hydroxymethylphenyl-(4-fluorophenyl)methanol (5a) as an oil.The resulting oil is dissolved in 600 ml of toluene andp-toluenesulfonic acid (10 g) is added. The reaction mixture is heatedto reflux and water is removed by azeotropic distillation. After thecompletion of the reaction the reaction mass is washed with 100 ml of10% aqueous sodium hydroxide solution, water (100 ml) and dried overanhydrous sodium sulfate. Solvent is removed completely under reducedpressure to get 5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (2a)as a pale yellow oil.

Yield: 95-100 g

HPLC purity: 90-92%

In the same way, other halogenated solvents like chloroform, ethylenedichloride chlorobenzene were used as a co-solvent in place of methylenedichloride to produce 5-bromophthalane. The yield and purity of5-bromophthalane (2a) made by using these solvents is given in Table 1:TABLE 1 5-Bromo- phthalane Sub- purity Sl. No phthalide Solvent mixtureby HPLC Yield 1 (5-bromo- *Tetrahydrofuran (THF) 80.5%   56% 2phthalide) THF: Methylene dichloride 92.5% 69.3% 3 THF: Ethylenedichloride 86.5%   65% 4 THF: Chloroform 92.2% 72.9% 5 THF: Toluene82.5% 58.3% 6 THF: Chlorobenzene 78.5% 58.3% 7 THF: Benzene 82.5% 58.3%*Prior art processThe isolated 5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran can beconverted to 5-cyanophthalane as per known processes, e.g. thatdescribed in U.S. Pat. No. 4,136,193, to provide pure 5-cyanophthalane.

EXAMPLE 2 Preparation of pure5-Cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (2b) UsingHalogenated Solvents

A solution of 4-fluorophenyl magnesium bromide prepared from 153.33 g4-fluoro bromobenzene (0.876 moles), 25.33 g magnesium turnings (1.055moles) and 0.05 g iodine in dry 300 ml tetrahydrofuran, is added to asuspension of 100 g 5-cyanophthalide (0.628 moles) in 1000 ml methylenedichloride at −6 to −2° C. and worked up according to the method ofExample 1, resulting in a thick semi-solid. This is triturated with 500ml of isopropyl alcohol (IPA) and cooled to 0-5° C. to provide5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (2b) as a solid.This solid is filtered and washed with cold 50 ml of IPA.

Yield: 130-140 g

HPLC purity: 99.32%

In the same way other halogenated solvents like chloroform, ethylenedichloride chlorobenzene were used as a co-solvent in place of methylenedichloride to produce 5-cyanophthalane. The yield and purity of5-cyanophthalane made by using these solvents is given in Table 2: TABLE2 5-Cyano- phthalane Sub- purity Sl. No phthalide Solvent mixture byHPLC Yield 1 (5-cyano- *Tetrahydrofuran (THF) 95.6% 29% 2 phthalide)THF: Methylene dichloride 99.32%  86% 3 THF: Ethylene dichloride 99.12% 85.0%   4 THF: Chloroform 99.35%  86.5%   5 THF: Toluene 97.5% 70% 6THF: Chlorobenzene 94.2% 78% 7 THF: Benzene 93.5% 78%*Prior art process

EXAMPLE 3 Isolation of 4-cyano-2-hydroxymethylphenyl-(4-fluorophenyl)methanol (dihydroxy compound 5b)

A solution of 4-fluorophenyl magnesium bromide prepared from 153.33 g4-fluoro bromobenzene (0.876 moles), 25.33 g magnesium turnings (1.055moles) and 0.05 g iodine in dry 300 ml tetrahydrofuran, is added to asuspension of 100 g 5-cyanophthalide (0.628 moles) in 1000 ml methylenedichloride at −6 to −2° C. After the reaction is completed, the reactionmass is quenched with 100 ml 20% aqueous ammonium chloride solution. Theorganic layer is separated and diluted with 100 ml of methanol. Slowly,12 g of sodium borohydride (0.324 moles) added over a period of one hourat below 25° C., and the same temperature is maintained for 4-6 hours.The mixture is then cooled to 5-10° C., maintained for 2 hours and thenthe precipitated solid is filtered. The solid is washed with cold waterand dried under vacuum below 40° C. to provide pure4-cyano-2-hydroxymethylphenyl-(4-fluorophenyl)methanol (5b).

Yield: 115-120 g

HPLC purity: 99.2%

EXAMPLE 4 Synthesis of5-Bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (2a) Using AromaticHydrocarbons as Co-Solvent

A solution of 4-fluorophenyl magnesium bromides prepared from 116 g4-fluoro bromobenzene (0.662 moles), 18.81 g magnesium turnings (0.78moles) and 0.05 g iodine in dry 300 ml tetrahydrofuran, is added to asuspension of 10 g 5-bromophthalide (0.469 moles) in 1000 ml of tolueneat −6 to −2° C. After the reaction is completed, the reaction mass isquenched with 100 ml 20% aqueous ammonium chloride solution. The organiclayer is separated and diluted with 100 ml of methanol. Slowly, 12 g ofsodium borohydride (0.324 moles) is added in lots over a period of onehour at below 25° C. and the temperature is maintained for additionalone hour. The reaction mass is quenched with 200 ml ice water. Theorganic layer is separated washed with dilute hydrochloric acid (10%,100 ml) and then with 100 ml water. To the resulting toluene layer,p-toluenesulfonic acid (10 g) is added. The reaction mixture is heatedto reflux and water is removed by azeotropic distillation. After thecompletion of the reaction, the mass is washed with 100 ml of 10%aqueous sodium hydroxide solution, water (100 ml) and dried overanhydrous sodium sulfate. Solvent is removed completely under reducedpressure to provide 5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran(2a) as a pale yellow oil.

Weight: 80-85 g

Purity by HPLC: 82.5%

The above-obtained oil is dissolved in 200 ml hexane at 45-50° C. andcooled to 0-5° C., which is maintained for 3-4 hours. The slurry isfiltered and washed with 50 ml chilled hexane and dry under reducedpressure.

Weight: 65-70 g

Purity by HPLC: 97.5%

Melting point: 38-40° C.

EXAMPLE 5 Synthesis of5-Cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (2b) Using AromaticHydrocarbons as Co-Solvent

A solution of 4-fluorophenyl magnesium bromide prepared from 153.33 g4-fluoro bromobenzene (0.876 moles), 25.33 g magnesium turnings (1.055moles) and 0.05 g iodine in dry 300 ml tetrahydrofuran, is added to asuspension of 10 g 5-cyanophthalide (0.628 moles) in 1000 ml toluene at−6 to −2° C. and worked-up as explained in Example 4 to provide a thicksemi-solid. This is triturated with 500 ml of isopropyl alcohol (IPA)and cooled to 0-5° C. to provide 2b as a solid. The solid is filteredand washed with 50 ml of cold IPA.

Dry weight: 105-110 g

Purity by HPLC: 97.5%

1. A process for the preparation of a5-substituted-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran comprising:(a) carrying out a Grignard reaction on a 5-substituted phthalide in aco-solvent system, comprising adding 4-fluorophenyl magnesium halide inan ether solvent to a 5-substituted phthalide in an organic co-solventto the ether solvent, to form a4-substituted-2-hydroxymethyl-4′-fluorobenzophenone, (b) carrying out aketone reduction of the4-substituted-2-hydroxymethyl-4′-fluorobenzophenone following theGrignard reaction, to form a4-substituted-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanol, and (c)carrying out a cyclisation reaction on the4-substituted-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanolfollowing the reduction reaction, to form a compound having thestructure:

wherein R represents Br or CN.
 2. A process according to claim 1,wherein the co-solvent is selected from the group consisting of analiphatic chlorinated solvent, an aromatic chlorinated solvent and anaromatic hydrocarbon.
 3. A process according to claim 2, wherein theco-solvent is an aliphatic or aromatic chlorinated solvent selected fromthe group consisting of methylene dichloride, ethylene dichloride,trichloroethane, carbon tetrachloride, chloroform, chlorobenzene,dichlorobenzene, and mixtures thereof.
 4. A process according to claim3, wherein the co-solvent is at least one of methylene dichloride andchloroform.
 5. A process according to claim 2, wherein the co-solvent isan aromatic hydrocarbon selected from the group consisting of toluene,benzene, xylene, and mixtures thereof.
 6. A process according to claim1, wherein the ether solvent and co-solvent are both dry.
 7. A processaccording to claim 1, wherein the volumetric ratio of ether solvent toco-solvent is between 3:10 and 6:7.
 8. A process according to claim 1,wherein the ether solvent is selected from the group consisting of1,4-dioxane, diethylether, dimethoxyethane and tetrahydrofuran (THF). 9.A process according to claim 1, wherein in the ketone reduction step(b), between 0.25 and 1.0 molar equivalents of sodium borohydride areused as reducing agent.
 10. A process according to claim 9, wherein inthe ketone reduction step (b), 0.5 molar equivalents of sodiumborohydride are used as reducing agent.
 11. A process according to claim1, wherein the cyclisation reaction (c) comprises the use ofconcentrated hydrochloric acid or an organic acid selected from thegroup consisting of methanesulfonic acid, benzenesulfonic acid andpara-toluene sulfonic acid (PTSA).
 12. A process according to claim 11,wherein the acid is used in a catalytic amount.
 13. A process accordingto claim 12, wherein the acid is PTSA in a catalytic amount of 5 to 10%w/w with respect to the 5-substituted phthalide.
 14. A process accordingto claim 1, wherein the Grignard reaction (a) is carried out at atemperature of from −6° C. to −2° C.
 15. A process according to claim 1,wherein in the Grignard reaction (a), the molar ratio of 4-fluorophenylmagnesium halide to 5-substituted phthalide is 1:1 to 1.4:1.
 16. Aprocess according to claim 1, wherein the entire process, comprisingGrignard reaction (a), reduction reaction (b) and cyclisation reaction(c), is carried out in a reaction vessel without isolation ofintermediates from solution.
 17. A process for preparation of4-bromo-2-hydroxymethylphenyl-1-(4-fluorophenyl) methanol or4-cyano-2-hydroxymethylpheny-1-(4-fluorophenyl) methanol comprising: (a)carrying out a Grignard reaction on a 5-substituted phthalide in aco-solvent system, comprising adding 4-fluorophenyl magnesium halide inan ether solvent to a 5-substituted phthalide in a suitable organicco-solvent to the ether solvent, to form a4-substituted-2-hydroxymethyl-4′-fluorobenzophenone, and (b) carryingout a ketone reduction of the4-substituted-2-hydroxymethyl-4′-fluorobenzophenone with sodiumborohydride, to form a compound having the structure:

wherein R represents Br or CN.